5-alkoxy-alkyl, 5-cyclohexyl hydantoins



Patented Feb. 1, 1949 5-A LKXY -ALKYL, E-CYGLOHEXYL a H YDANTOINS Henr'y RQH'enZe, Austin, Tex.,"assignor to Parke. Davis (fit-Company, Detroit, Mich, a corporation of Michigan st mati g. Zipplicationduly 10, 1944, r Serial'No.544,331

:The invention relates to a new' class of chemical compounds which are valuable for therapeutic use, especially as .anticonvulsants. having relatively high anticonvulsant activity combined with low toxicity. p

The compounds of the invention have the general formula ROCHz OON-M H2 H: G H: \NHQO a H2 I where R represents an I alkyl radical 'of the straight or branched chainseries'having 1 to 6 carbon "atoms including cyclohexyl. ".Mrof this formularepresents a member of the class hydrogenand: bas'i-celem'ents or groups forming nontoxic salts of the hydantoins, such as sodium, calcium, magnesium, ammonium and substituted. ammonium, iorexarnple, mono.- and dialkyl ammonium and corresponding hydroxy alkyl ammonium. p

In preparing the compounds of this invention, I preferito first prepare the corresponding al'koxytnethyl-S-phenyl hydantoins as set forth in my. copending applications, Serial Nos.'535,743 and 535,744, both filed May 15, 1944. These phenyl hydantoins are prepared byreacting the corresponding ketone i-ntermediate"of the'ior- 4. claims. {01.2.60-3095).

rnula given above for the final products, with an alkaline water-soluble cyanide and aqueous am; nionium carbonateor the like ccmbination'consisting of, or capable of generating, NHs, carbon dioxide, and water, acidifying the reaction rniX-T ture; and separating the hydantoin. The inter;

mediate ketones are, in most cases, preparedby the action of phenyl Imagnesium. halide 1a This may require from 4 to '20 hoursbut is. 115 11% ally completed in 6.-? hours. The bottlelofthe hydrogenatoris then opened and the catalystfiltered from the solution. 111C388 the resulting cyclohexyl hydantoin is sumciently 'less soluble 0 to cause it to separate from the solution prior to;

the-abovefiltration step, the mixture is warmed: before filtration. After filtering, the cyclohexyl. hydantoins may be separated from the; alcoholicfiltrateby dilution with water and recrystallizingfrom diluted ethyl alcoholj The new 5.-alkoxymethyl-5-cyc1ehexyl hydantoins of: the presentinventiorr have tl egpropefl; ties'skioifii in the following table"whre the symg.

-. bol R is thesameas in the general fonrmlai mule, I above: 2

5Alkoxymethyl5-Cyclohexyl Hydantoins Carbon, per- Hydrogen, per- P. 00 cent cent (con) Calcd. Found Oalcd. Found CH CH 191. 5-192 0 59.98 59.89 8.38 8. 41

CH;CH;OH 183. 0-183 5 61.39 61.20 8. 72 8. 72 -CH(OHz)a- 220 61.39 61.30 8.72 8.84

--CH2CH:CH2CH3 177 62. 66 62. 8. 98 9. 10 'OH2CH(CH 213 62.66 62. 56 8.98 9. 04

H(OH )CH:CH3 240 62. 66 62. 51 8.98 9.05

OH2CH:GH2OH1CH 152. 0-152. 5 63.80 63.85 9. 28 9. 21

--CH(CH )CHzOHzOHz.. .H. 208. 0-208. 5 63.80 63.72 9. 28 9. 25

-OH(GHCH;): 245. 0-245. 5 63. 80 63. 9. 28 9. 33

-OH1(OH1)4GH3 177 64. 83 64. 9. 52 9. 60

-CaH13 (cyclo) 254. 0-254. 5 65. 27 65. 25 8.90 9.00

The preparation of the compounds of this invention is more fully illustrated in the following example relating to 5-ethoxymethy1-5-cyclowhere R has the same signifiance as in the for- 55 hexyl hydantoin.

cyclohexyl hydantoin Ethoxymethyl phenyi ketone having a boilin tained from ethoxyaeetonitrile andphenyl mag nesiumbromide.

One mole f ethoxymethyl phenyl ketone is twomoles of potassium cyanide in water. About three moles of ammonium carbonate areadded 16 hours. The reaction mixture is then "cooled and acidified with dilut sulfuric acid under a The product can be purified by dissolving it in 7 water containing sodium hydroxide, the solution treated with decolorizing charcoal, filtered, and

the filtrate treatedwith carbon dioxide to precipitate pure White 5-ethoxymethyl-5-phenyl hydantoin havingla melting point of 191.6 C.

"0,25%030 g. of Adams platinum catalyst is placed inthe bottle'of a hydrogenator and covered with 80 cciof 95% alcohol. The bottle is closedand hydrogen introduced up to pressure of ,90l'in n.v The shaker is thenstarted and the platinum "oxideis reduced to the ;metal., The

shaker is then stopped, the container opened and afsolution of 19 g. of 5-ethoxymethyl-5-phenyl hydration in 100 cc. of 95% alcohol and 1200. of

The hydrogen pressure is again raised to 900 mm. and the "shaker started and continued as long as is occurring Complete hydrogenation is usually attainedin' 6" or '7 hours. The. bottle is then opened and the catalyst filtered from the solution and'the filtrate diluted with water to precipitate 5 .-etho'xymethyl-5-cyclohexyl hydantoin. After recrystallization from diluted ethyl alcohol it has a melti'ng point of 191.5-192-.0 C. When mixed with 5 ethoxymethylr-5 phenyl hydantoin it has a meltin-gpoint of 160-165? C. The yield obtained in the hydrogenation is 90-95%. l r V 7 ph y Thesodium salts of each of the hyd -p'gint of about 122 C. at mm. pressure is ob- V placed in 800 cc. of ethyl alcohol and to this added a cyanide solution containing slightly over 'b'e'administered perorally or parenterally as by and the reactant warmed at 55-60.? C..for about hood. Hydrogen cyanide is evolved. The result- 1 ing precipitate is cooled and washed with water. 5'

concentrated hydrochloric acid is introduced.

, ajd'rop in; hydrogen pressure shows that reduction;

wiltin Emmple.-Preparation of S-ethoxZ/mdhgl-i droxide, an alkaline earth metal hydroxide, am-

monium hydroxide organ amine toobtain the corresponding salts indicated in the general formula under the symbol M.

e The therapeutic agents of my invention, either inthe'form of the hydantoins or their salts, may

injection. They can be suspended or dissolved in inert carrier liquids; such as in aqueous solution or in suspension in animal or vegetable oils or fats before administration. In general, the

-dosageperorallyof the hydantoins and their so- 'fdiumsaltsis in the neighborhood of one or two grams per day for an adult person, given in divided doses of about one-third to about onehalf gram per dose. However, the exact dosage will vary .withthe individual .and with the particular hydantoin used. I

-- What I claimas my invention is:. I ;1. .A'compoundv having the formula noom QO -N M NH-oo REFERENCES crr n I 4o r .1 The'following references'are of record in the file of this patent: V g

e 7 e UNITEDSTATES PA'I'ENTS V Number Name Date Y 2,155,863 Jacobson Apr. 25', 1939 2,327,890 'Henze Aug. 24, 1943' the nQQTI-IER. EFEannd sf *--vol. 65, page 324. 

